There is now significant evidence that NMDA glutamate transmission is involved in the behavioral effects of morphine. For example, inhibition of NMDA receptors alters the antinociceptive and discriminative stimulus effects of morphine, and tolerance to these effects under certain conditions. The ability of NMDA receptor inactivation to alter morphine's effects has attracted significant clinical attention. Currently, drugs that target the NMDA receptor are in clinical trials for their ability to improve morphine analgesia and as treatments for morphine dependence. To date, manipulations for assessing NMDA receptor involvement in the behavioral effects of morphine have been limited to pharmacological inhibition of the NMDA receptor. The proposed study further examines the role of NMDA receptors in the behavioral effects of morphine in mice with a partial deletion in the gene encoding the NR1 subunit of the NMDA receptor (NR1-KD). The aim of the current proposal is to assess NMDA receptor involvement on behavioral endpoints related to morphine analgesia and the subjective effects of morphine that are thought to contribute to abuse. Specifically, these studies systematically assess morphine antinociception and the discriminative stimulus effects of morphine in a genetic model of NMDA deficiency. Specific Aim I tests the hypothesis that disruption of NMDA receptor function alters the antinociceptive effects of morphine after acute and chronic morphine administration in NR1-KD mice, enhancing our understanding of NMDA-mediated mechanisms in morphine analgesia. Specific Aim II tests the hypothesis that the NMDA system plays a role in the discriminative stimulus effects of morphine, enhancing our understanding of NMDA-mediated mechanisms in the subjective effects of morphine. The experiments detailed in this proposal will provide novel data concerning NMDA receptor mechanisms in clinically relevant behavioral effects of morphine. Together, these investigations are designed to systematically assess NMDA receptor involvement in the analgesic effects of morphine as well as morphine's subjective effects that are thought to contribute to its abuse. Findings from these experiments may have important clinical implications, and may lead to new pharmacotherapeutic strategies in the treatment of pain and drug abuse. [unreadable] [unreadable] [unreadable]